JPS6045577A - 2-azabicylo(2,2,2)octane derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the following formula I: phenylalkoxycarvinyl having 1 to 4 carbon atoms in the blank xy moiety, 01 to 6 alkyl, 1 to 6 alkyl in the alkyl moiety;
is aralkyl or substituted acyl having ~4 carbon atoms, R1 is hydrogen or C1-4 alkyl, is hydrogen or halodane, X is hydrogen or halogen, Y is hydrogen , or X and Y - together represent a carbon-carbon bond, W is alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, cyano, cardexamide or haloformyl, or X represents a halogen. 2-azabicycloC2,2,2]octane derivatives (where X and Y together represent a -C-O group)1.

According to another aspect of the invention, there is provided a method for producing the above compound.

The compounds of formula (1) are themselves biologically active and have particularly valuable antispasmodic, vasodilating, immunosuppressive or gastric acid secretion suppressing effects. On the other hand, those compounds also contain 2-azabicyclo[2,2
, 2] useful in the production of other biologically active compounds having an octane skeleton.

According to yet another aspect of the invention, there is provided a pharmaceutical composition comprising as an active ingredient at least one compound of formula (1) as defined above, together with a pharmaceutical carrier or excipient.

In the compounds of formula (1), the term "alkoxy" is used alone or as part of other groups, and refers to straight-chain or branched alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, A as O 01-6 alkyl, which means isopropoxy, n-butoxy, isobutoxy, tert-butoxy group, is a straight chain or branch 01
~6 represents an alkyl group, such as a methyl, ethyl, n-zolopyl, isozolobyl, n-butyl, isobutyl, tert-butyl, n-pentyl, impentyl, n-hexyl or isohexyl group. Such groups can also be represented by R1 when R1 represents a C1-4 alkyl group, with the exception of n- or isohexyl groups.

The alkyl group having from 1 to 4 carbon atoms in the alkyl moiety represented by A is - or more monocyclic or polycyclic, spaced or fused, carbo- or heterocyclic aryl group. , especially an indolyl group.

The term "substituted acyl" in the present invention refers to substituted aryl (
C2_4alkoxy)carbonyl group, in which the aryl moiety has the meaning defined above, and is preferably indolyl. Preferably, the substituent contains a rhodone, lower alkyl, lower alkoxy group, and the like.

As halogens, 2 and represents a carbon bond, R1, Z and W have the meanings as defined above) are represented by the formula (■): 1, where R1 and R1 have the meanings as defined above; It is obtained by reacting a 2-dihydropyridine derivative with an acrylic derivative represented by the formula (■): (wherein W and 2 represent the meanings defined above). This reaction is a cycloaddition, where the group A attached to the nitrogen of the compound of formula (It) is a protecting group, which stabilizes the dihydropyridine structure. As a result, the compounds are more resistant to atmospheric oxygen and easier to handle.

The resulting compound of formula (1), in which w is a haloformyl group and the other substituents are as defined above, is hydrolyzed (optionally without separation) to the corresponding acid and further compound of formula (I) (in the formula, W and Y together represent a 10-0- group, and X represents a halo-9 group) can be converted into the corresponding halolactone [a,)].

Formulas (n) and (■) (in the formulas, jljc, ~4 alkoxy, and 8 are phenyl (01-4 alkoxy) carbonyl groups, Yes, W is (C1-4 alkoxy) carbonyl,
The compound of formula (1) obtained by reacting the compound of formula (1) in which cyano or shikkekal is a xamide group and further has the meaning defined above for R1,
) is reduced on formula (1) (wherein 2 is halodane)
The corresponding compound is a (C4-4 alkoxy) carbinyl group, X and Y together represent a carbon-carbon bond, hydrogen or halogen, W represents a no-roformyl group, and R4 has the meaning defined above)
The compound of is converted into the corresponding ester derivative by adding an aliphatic alcohol having 1 to 4 carbon atoms, optionally without separation, or phenyl (C4
~4 alkoxy) carzenyl group, X and Y together represent a carbon-carbon bond, 2 is hydrogen or halogen, W represents a cyano group, and R1 has the meaning defined above. ) is the corresponding acid amide (W=cal?).
represents a xamyl (C5-4 alkoxy) carbinyl group,
Together, X and Y represent the entire carbon-carbon bond, and R,
, Z and W have the meanings defined for formula CI)) can be prepared by removing the protecting group A'(il-) under acidic conditions. ) can be converted into the corresponding 2-azabicyclo-[2,2,2]-oct-5-ene [b1]. If desired, the obtained compound can be converted into an acid addition salt.

Alternatively, the protecting group can be removed by catalytic hydrogenation using excess hydrogen. In this reaction,
Upon removal of the protecting group, the X-Y double bond is saturated and furthermore, if 2 is halogen, it is replaced by hydrogen C R2) 'II.

Compounds of formula (1) (wherein the human is hydrogen, X and Y together represent a carbon-carbon bond, and R1, Z and X have the meanings defined above), or their The double bond in the acid addition salt can also be saturated by catalytic hydrogenation with a stoichiometric amount of hydrogen.

If desired, the formula (I) (in the formula is hydrogen, and furthermore, X, Y
. (representing aralkyl or substituted acyl having 1 to 4 carbon atoms).

Many alternative methods are known to those skilled in the art for the production of 2-azabicyclo[2,2#2]-octane (inquinuclidine) skeletons. The first method is by Ferbel and Bruckner (Chem, Ber.

76B, 1019-1027 (1943)).

Starting from a cyclohexane aminocaldenic acid derivative,
A disadvantage of the inquinuclidine synthesis developed by Felpel and Bruckner is that the ring closure is carried out at very high temperatures. Another drawback is that although inquinuclidones are obtained, selective removal of oxygen from the acid amide is a difficult problem.

Furustos et al. [Tetrahedron Letter
s 1970°1263; 1bid 1972.9
93-996; Bull, Soc.

Chlm, France 1974.2485-94
; Can, J.

Chem-1976, 3576, 3569-79: C
, R.Acad.

Set, 5er-C, 1971, 273 (6) 47B
-80] discloses the use of N-chloro-N-methyl-aminomethyl-cyclohexene derivatives as starting materials for the ring closure reaction. The disadvantages of this method are as follows. That is, in addition to the desired inquinuclidine, another azabicyclo derivative is formed.

Isoquinuclidine derivatives also include, for example, aziridines (J,
Am, Chem=Soc, 1967r 504
6-48: Same as above 1968.1650-51: French patent 1,572,766), 1-azidor) le? Lunan (J, Org, Chem.

1971, 2864-69); 1-N,N-dichloroaminoapocamphane (J, Am, Chem
, Soc, 1972+7599-7600; Ibid. 1973.3646-51) can also be obtained by ring conversion from cyclic compounds having different skeletons. These reactions again give rise to more different products.

Inquinuclidine scaffolds are most often produced by the Diels-Alder reaction. If the genophile contains nitrogen, it usually reacts with cyclohexadiene. In the study of this reaction type, K. Gut et al. conducted pioneering research.

By reacting methylene diurethane with cyclohexadiene in the presence of boron trifluoride, they prepared 2-carbetoxy-2-azabicyclo-[2°2.2]oct-5
-ene was obtained (Chem, Ind.

1964.1422-23: J, Org, Ch.
em, 196L1422-23; J, Org,
Chem, Su65.3772-75).

According to various variants of the above method, type R'R"C=N
Various compounds of R'' are used as genophiles (A
cta Chem, 5cand, 196L 258
5-90 ; Tetrahedron Letters
1976, 3309-11).

Crow investigated the cycloaddition reaction of genophiles of type R'CH=NR (J, Chem, 8oc, 19
73゜5273-80: Tetrahedron L
etters+ 1974e2977-81 ; J-O
rg, Chem, 1977-2486-91;T
atrahedron Letters 197L 1
971-74).

If the diene contains the nitrogen necessary for the formation of the inquinuclidine backbone, a substituted 1,2-dihydropyridine is generally reacted with a genophile containing a maleic acid conductor, such as maleic acid (Izv, Akad).
, Mauk, 5SSRSer, Khlm.

1964, 1322-24), maleic anhydride (I
zv.

Alcad, Nauk, 5SSRSer, Khi
m, 1964.1322-24; J, Am, C
hem, Soc, 1961. '449-53;
J.

Org, Chem, 1962. 320-21)
, maleic imide (J, Org, Chem, 19
62=1439-41): FuFA/acid derivative,
For example, methyl fumarate (Tetrahedron Let
ters 1977e 4129-32); acrylic acid derivatives, such as methyl acrylate (J, Med,
Chem, Iβ374-78), ethyl acrylate (J, Med, Chem.

1977, 682-86; U.S. Patent 4,100,16
4; Canadian Patent No. 1,052,785), acrylonitrile (Helv.

Chem, Acta 1962+ 1344-51
; Tetrahedron Letters 196'
6+ 6385-91; same as above 3383-86: Ch
em-Comm, 1969+ 88-89. US Patent 3β16,439゜Japanese Patent Specification 7,519,770
); Methyl vinyl keto y (J, Am, Chem,
Soc, 1965.2073-75. Same as above 196L
3090-109 ; Tetrahedron Le
tters1977=4299-300); and acrolein (Tetrahedron Letter
s 1979.2485-88).

Japanese scientists, Headquarters et al., announced a new synthetic method for the production of inquinuclidone compounds: they reacted 2-piperidone with all different genophiles (Tetr
ahedron Letters+ 1969#246
5-68; Chem, Pharm, Bull,
1970.925-31; i b id, 197
2 + 226-31: Japanese Patent Specification 7.413,
799 ++, Heterocycles 1977
e 267-6LChem, Pharm, Bull
, 1979.670-75).

As a summary of the above soil addition reactions for the production of inquinuclidine scaffolds, it can be concluded that nitrogen-containing genophiles are generally difficult to produce.

Reactions starting from 2-pyridine or its derivatives as nitrogen-containing diene do not give very good results. Because these reactions give the corresponding inquinuclidone compounds, it is further a problem to selectively remove the effects of excess oxygen.

The Diels-Alder reaction starting from a dihydropyridine derivative is somewhat more convenient since the starting pyridine derivative can be easily prepared.

Surprisingly, we found the following facts.

That is, a compound having a 2-azabicyclo[2,2,2]octane skeleton can be synthesized from N-alkoxycarvinyl-31N-aralkoxycarbyl in good yield from readily available starting materials. It is obtained by reacting nyl-1,2-dihydropyridine with acrylic acid or a 2-haloacrylic acid derivative. Further derivatives can be obtained by modifying the 7-substituted product of the obtained 2-azabicycloC2,2°2]oct-5-ene derivative. In this way, for example, ester, halolactone, cyanide or acid amide derivatives can be obtained. In addition, the double bond of 2-azabicyclo(2e2.2)octene derivatives can be disaturated by hydrogenation.

Optionally, protecting groups can be added to the resulting 2-azabicycloC2
,2,2) can be removed from the nitrogen of the oct-5-ene derivative, and the resulting unprotected compound can be isolated in the form of a salt.

If desired, removal of the protecting group and 2-azobiccyclo[2
, 2, 2] The saturation of the double bonds of oct-5-ene derivatives can be carried out simultaneously, and furthermore, from unprotected octene or octane derivatives or their acid addition salts, novel N-alkyl, N-alkyl Alkyl and N-acyl derivatives can be obtained by conventional alkylation, aralkylation or acylation reactions.

According to the present invention, N-alkoxycarbonyl- or N-aralkoxycarboxylic acid of formula (tl)? Nyl-1,2-dihydropyridine is used as starting material. This compound was developed by Forel (J, Org.

Chem, 1972.1321-23). Preferably N-ethoxylic? 2#-3?
Ji-N-penzyloxycarbunyl-1,2-dihydropyridine is used as a solution in an inert solvent, preferably acetonitrile. According to a preferred embodiment, the formula (I
II) acrylic acid derivatives or 2-haloacrylic acid derivatives, preferably 2-chloroacrylic acid chloride, 2-
Chloroacryloridonyl or methyl acrylate is added to the solution. Alternatively, the dihydropyridine derivative of formula (II) can be dissolved in excess genophile of formula ([1)].

The reaction is carried out at room temperature) or, in the case of less reactive genophiles, at a slightly elevated temperature, for example from 60 DEG to 90 DEG C., with stirring. The cycloaddition reaction is monitored spectroscopically or by thin layer chromatography.

If the addition reaction is carried out using an acrylic acid chloride of formula (III), the acid chloride derivative is preferably 1
The corresponding alcohol having ~4 carbon atoms is added to the reaction mixture, which is then converted into the corresponding ester by stirring for several hours and further evaporation.

From the evaporation residue obtained by the above modified reaction method, the formula (1
) is isolated by several extraction or chromatographic purification steps.

When producing a halolactone of formula (I) (W and Y together represent a 10-0- group and further represent and the product obtained is further converted into the corresponding acid by adding water to the reaction mixture. From the organic solution, the corresponding salt of the carnic acid derivative of formula (r) is obtained by aqueous alkaline extraction, preferably carried out with saturated potassium bicarbonate solution, which is then converted into the corresponding halodane, Preferably bromine iodide or potassium iodide/
The iodine solution is converted to the desired halolactone by addition to the aqueous solution. The precipitated rolactone of formula (1) is recrystallized from a customary organic solvent, preferably ethanol.

To obtain the amide of formula (I), the nitrile of formula (1) is
It is dissolved in a water-miscible organic solvent, preferably dimethyl sulfoxide, and then an aqueous solution of a strong base, preferably potassium hydroxide, is added to the solution. The mixture is stirred for several hours and the precipitated acid amide of formula (1) is filtered off and, if desired, recrystallized from customary organic solvents, preferably ethanol.

If the halodane in place of Z in the compound of formula (1) is replaced by hydrogen, the compound of formula (1) is preferably reduced by boiling with zinc in a solution containing glacial acetic acid.

Optionally, 2-azabicycloC2,2,2: ] ] to protect the nitrogen of the octo-5-ene derivative.
or an aralkoxylic acid in which the nyl group is removed as follows: in an acidic medium, preferably glacial acetic acid containing a scale of bromide (
By completely treating the N-alkoxy- or N-aralkoxycarbunyl compound of I), the substituents z, w, x,
The obtained compounds of formula 0 (summer), giving the corresponding N-unprotected compounds without affecting y and R1, are then converted into their acid addition salts by known methods.

If in a compound of formula (I), where X and Y together represent a carbon-carbon bond, removal of the °'A" alkoxy- or aralkoxycarmenyl protecting group
If the double bonds of the alkoxyl or UN-alkoxycardenyl-2-azabicyclo(2,2,2)oct-5-ene compounds are to be simultaneously saturated, the reaction is preferably carried out using charcoal-supported radium or laneini, It is carried out by catalytic hydrogenation in the presence of Kel catalyst. If 2 in the starting compound used in this reaction represents a halogen, it is simultaneously replaced by hydrogen with removal of the "A" protecting group and also saturation of the double bond. If desired, these compounds can be converted into the corresponding acid addition salts.

If a compound of formula (I) (in which the nitrogen atom is not protected, X and Y represent hydrogen, and 2 is a halogen) is prepared entirely, the compound of formula (■) (in which the nitrogen atom is not protected and X and Both Y represent a carbon-carbon bond and 2 is halodane). In this case, the catalytic hydrogenation is carried out with a stoichiometric amount of hydrogen using radium supported on charcoal as a trench catalyst. In this reaction, the double bond of the 2-azabicycloC2,2',2)oct-5-ene derivative is saturated, but the halodane atom in place of Z remains unchanged. If desired, the resulting compound can be converted into the corresponding acid addition salt.

The unprotected 2-azabicyclo[
2,2,2]octane derivatives, or their acid addition salts, by dissolving them in a polar organic solvent, preferably alcohol or acetonitrile, and then treating them with an organic base, preferably triethylamine. By N
- Can be alkylated. The corresponding alkyl or aralkyl halide is added to the resulting solution and the mixture is then left at room temperature. The course of the reaction was monitored by thin layer chromatography, the reaction mixture was then evaporated, the precipitated salt of the amine was filtered off, and the N-alkyl- or N-aralkyl-2-azabicycloC2,2,2
The 3-octane derivative is isolated by total evaporation of the mother liquor, then optionally recrystallized from customary organic solvents or mixed solvents and optionally further purified by p-chromatography.

2-azabicyclo[2,2
, 2] octane derivatives, or their acid addition salts, can be acylated by techniques commonly used in 4zotide synthesis: the corresponding base can be liberated from the acid addition salt, and further acylation can be carried out using piperyl chloride. can be carried out using a mixed anhydride obtained from an organic acid, preferably the acid indolyl acetic acid. The reaction is the acid used, preferably indolyl acetic acid? Dissolved in a dipolar aprotic solvent, preferably dimethylformamide, add an organic base, preferably triethylamine to the solution, cool the resulting solution preferably to -5 to -10 °C, and add piperyl chloride dropwise. and then add dropwise a solution of the acid addition salt of the acylated 2-azabicyclo[2,2,21-octane conductor] in dimethylformamide P or triethylamine at low temperature, preferably between 5°C and 0°C. This is preferably done. The reaction mixture is stirred at room temperature, the precipitated triethylamine salt is filtered off and the filtrate is evaporated under reduced pressure.

The evaporation residue is dissolved in a water-miscible solvent, preferably ethyl acetate or a chlorinated hydrocarbon, washed with water, dried over magnesium sulphate, evaporated and the precipitated crystals are filtered off and washed. , dried and optionally recrystallized from a solvent or mixed solvent, preferably methanol or a mixture of n-hexane or ethyl acetate.

Acylation can also be carried out using indolyl acetyl chloride in the presence of triethylamine in a medium of cuchloromethane at room temperature, or using indolyl acetic anhydride in an acetonic medium.

The invention will now be explained in more detail in a non-limiting manner by means of the following examples.

Example 1 2-hensyl oxycarb is 2-AP4-ethyl A-7-40
Ru7-ethoxycarvinyl-2azabicycloC2,2
,2:]oct-5-ene21.49 (0.2 mol)
3-Ethyl-pyridine'i: Dissolve in 250 mJ of anhydrous methanol. To the resulting solution, 7.5 g (0.2 mol) of sodium tetrahydroborate powder was slowly added at below -65° C. with vigorous stirring in an argon atmosphere, followed by 28.8 ml of benzyl oo formate (
34,111,0.2 mol) is added. The reaction is highly exothermic. After the addition is complete, the reaction mixture is stirred for an additional hour and then carefully heated to room temperature. The reaction mixture is evaporated in vacuo. evaporation residue into ether 200ml
and then washed with 100 ml of water. The aqueous phase is extracted twice with 1007 d each of ether. - Wash the combined ethereal phases with 20 - of 1-thiacetic acid solution. pH of aqueous solution
5-6 after extraction. The ether phase is dried over magnesium sulphate and then evaporated in vacuo. The evaporation residue is
It is a mixture of N-benzyloxycarvinyl-1,2-,1,4- and 1,6-3-ethyl-dihydropyridine isomers.

UV spectrum (methanolic solution): λmax=30
5 nm 1, 2 and 1,6-3-ethyl-dihydropyridine λmax'' 260-270 nm unreacted 3-ethyl-pyridine λmax = 230-240 nm 1,4-dihydropyridine.

The weight of the evaporation residue is 36.7.9 (0,153 mol)
It is.

I]'tSpect#: 1700crn-N-C=O
: 1.470crn phenyl: 1100tynC-
0-C; 700crn, phenyl.

t, 1. c, (Kieserdal 60F154. Eluent:
Benzene and acetone 10:1 mixture, development: 254n
m UV light or iodine vapor): R, = 084 (1,2 and 1,6 isomers).

Evaporation residue k, dissolved in 150 mJ of anhydrous acetonitrile, then 24.4 g (0,194) mol of 2-chloro-acrylic acid chloride and O,1,! 9 of hydroquinone is added to the solution. The end of the cycloaddition is evidenced by the disappearance of the λmax=305 nm peak in the UV spectrum. Thereafter, 150 mf of anhydrous methanol is added to the reaction mixture, which is then stirred for three hours at room temperature. The acidic solution of PI (adjusted to 8-9 while cooling by adding triethylamine and then evaporated in vacuo. The evaporation residue is dissolved in 100 ml of benzene and then washed with 50 ml of water. The benzene phase is dissolved in sulfuric acid Drying over magnesium, filtering and evaporation in vacuo gives 59.9 g of an oily product which is then purified using Kieseldal 60 (0.06 g) using a 10:1 mixture of benzene and acetone as total eluent.
3-0.2+nm).

1 [sl: 19.3 II (35 II for 3-ethyl-pyridine).

IR filter (film): 1700rm = N
-0; 1470m phenyl; 1100L:rn C-0-C near 00 sub phenyl.

t, 1. c (Kieseldal 60 F254 + eluent: 10:1 mixture of benzene and acetone, development: 25
4 nm UV light or iodine vapor): R, = 0.85.
Margin example 2 below: 2-benzyloxycarvinyl-4-ethyl-7-chloro-7-cyano-2-azabicyclo[2s2.2:]]
Octo-5-ene, 3-ethyl-contaminated with 4- and 1,6-isomers
50 g (0.2 mol) of (N-benzyloxycarvinyl)-1,2-dihydropyridine are prepared as described in Example 1. This was then mixed with 1 g of hydroquinone for 2
-Dissolved in 60 g (0.69 mol) of chloroacrylic acid nitrile. The reaction mixture is protected from light and stirred in a 70° C. oil bath for 70 hours. The end of the cycloaddition is indicated by the disappearance of the λmax=305 nm peak in the Uv spectrum.

The reaction mixture is evaporated in vacuo and the residual oil is dissolved in 50 ml of benzene in a water bath at 50-60 DEG C. and washed with 50 ml of water and then twice with 50 ml each of benzene. The benzene phase is dried over magnesium sulfate and then evaporated in vacuo to give an oily residue. Kieselgl 60 (0
, 063-0.2 mm) and subjected to column chromatography using 30 times the volume. Fractions with R, greater than 0.75 were collected, evaporated and then purified with 4 of Kieselglu 60 (0.063-0.2 nm) using a 1:1 mixture of benzene and chloroform as eluent.
Subject to column chromatography treatment again at 0 times the volume.

The product obtained with R,=056 is isolated.

Yield: 8.5.17 (0.0257 mol), 13% based on starting 3-ethyl-pyridine.

t, 1. c, :Kieselglu 60 F254 *Eluent: 10:1 benzene/acetone, Rf=0.81
Developed with 21:1 benzene/chloroform R, = 0.56 iodine vapor or 254 nyn UV light.

IR System (Film) crn, 2300-CN
:1700 N-C=O; 1470 Ph; 700 Ph.

NMR spectrum (CDC43) ppm: 7.3 (
5 aromatic H-5,15(sbenzyl-CT(2-);
5.05 (d, H,).

Example 3 118.5 g (1.5 mol) of N-benzyloxycarbinyl-7-chloro-7-methoxycarginyl-2-abbicyclo[2,2,2]oct-5-ene in anhydrous pyridine were
00O' in anhydrous methanol, then 5711
．． 5 mol) of borohydride) IJium powder was heated at -65°C.
Add carefully at a temperature of
98 g, 1.75 mol) of benzyl chloroformate are added. The reaction is highly exothermic. Once the reaction is complete, the mixture is further stirred at -70°C and then carefully heated to room temperature. The evaporation residue was dissolved in 400 ml of ether, then 400 ml of water, 100 ml of 0.1 N hydrochloric acid solution.
m1! and then two more washes with 100 ml of water. The pH of the aqueous phase is approximately 5-6 after extraction. The ether phase is dried over magnesium sulphate and evaporated. UV spectrum of the evaporation residue containing a mixture of 1,2- and 1,4-dihydropyridine isomers dissolved in methanolic solution: λma! =305 nm 1 , 2-dihydropyridine.

Fuku&, = 260-270 nm unreacted bili-shin.

λmax230-240nrn 1,4-dihydropyridine.

Obtained evaporation residue 2489'fr, acetonitrile 7
00 ml and then add 192 F (1.54 mol) of 2-chloroacrylic acid chloride and 5 g of hydroquinone. The end of the cycloaddition is λmax”305 nm
This is indicated in the spectrum by the disappearance of the peak. After cooling, 400 ml of methanol are added to the mixture and it is left at room temperature for the working time.

The pH of the acidic solution is adjusted to 8-9 using triethylamine while cooling and then evaporated. The evaporation residue is dissolved in 500 m/l of benzene and then washed with 100 m/l of water. The benzene phase is dried over magnesium sulphate and evaporated. 442 g of oily product were obtained as evaporation residue, which was evaporated with toluene and ethyl acetate as eluent.
Using a 0:1 mixture vs Ki4-cell 1lv60 (0,0
63 to 0.2 m) column chromatography.

Yield: 95.9 (18.9%, 0.284 mol) Melting point: 285°C t, 1. c, (Kiesseldal 60f rate, eluent: 10:1 benzene/ethyl acetate, developed with iodine vapor)
: R,=0.6 IR spectrum: 1720crn Nisual C=O;
16906n Tsuktum C=O.

NM'R spectrum: 2.75 ppm (s -0
CH3) + 5.2ppm (8, benzyl-CH2-
).

6.3 ppm (m-olefin H-s).

7.4 ppm (aromatic H-s).

Side, Shimokinpaku Example 4 N-benzyloxycal? N-pennol obtained from pyridine 15.8 F (0.2 mol) as described in Example 3. oxycargenyl-1,
2-dihydropyridine is dissolved in 100- acetonitrile. 34 g (0.4 mol) of α-chloro-acrylonitrile and 2 g of hydroquinone are added to the solution, which is then stirred at 80° C. for 30 hours. Termination of cycloaddition is done by UV
This is indicated by the disappearance of the peak at λm@z = 305 nm in the spectrum. The reaction mixture is evaporated in vacuo.

The evaporation residue was dissolved in 150% of benzene and then 30% of water.
Wash with The benzene solution is dried over magnesium sulfate and evaporated in vacuo. The crude product is subjected to column chromatography on a Kiesel fl 60 (0.063-0.2 m) using a 10:1 mixture of toluene and ethyl acetate as eluent.

Yield: 14F (23.2%) Melting point: 68°C t, 1. a, (Kieserdal 60 plate, eluent: 10:1 benzene/ethyl acetate, developed in iodine vapor): R, = 0.6 NMR spectrum: 5.2 ppm (sbenzyl-CH2-) j
6.5 ppm (molefin H-s), 7.4 ppm
m.

(Aromatic H-i).

Example 5 2-benzyloxycal? N-benzyloxycal obtained as described in Example 3, N-7-promo-armethoxycarzanyl-2-azabicyclo(2,2,2)oct-5-ene, is converted into nyl-1,2-dihydropyridine 40Ji'(0,
2 mol), 38 Jil (0.23 mol).

Freshly prepared methyl α-bromo-acrylate and 2
Add 9 hydroquinone. The reaction mixture is left at room temperature for 48 hours, protected from light.

The end of the cycloaddition can be seen from the UV spectrum as λmaw = 30
Indicated by the disappearance of 5 nm. The reaction mixture was heated from 40 to
Evaporate in vacuo on a 50° C. water bath to an oily residue and then extract three times with 40 ml portions of a benzene/brine mixture. The benzene phase was dried over magnesium sulfate and then evaporated in vacuo, then chromatographed on 30 times the volume of Kiesergl (0.063 - 0.2 ■) using a 10:1 mixture of benzene and ethyl acetate for elution. Leave it to processing.

Yield: 8 g (0.01 mol), 11 based on starting pyridine
%t, 1. c, (Kieserdal 60F254 l Mercart, 5735: eluent: 10:1 benzene/ethyl acetate): R, = 0.75 IR spectrum (film) ctn-1: 174 oc = o; 170
0 N-C=0.1405 and 705 monosubstituted phenyl, 1250 -O-CH3° NMR spectrum (CDCl2) pPm: 7.3
(s, Ar(t5)): 6.4 (m H, Hl): 5
．． 2 (benzyl CH2): 4.05 (m, Hll) 3
．． 65 (OCH3g).

Example 6 N-ethoxycargenyl-7-chloro-7-cyano2
-Azabicyclo[2,2,2]oct-5-enbenzyloxycal is replaced by nyl chloride, and ethoxylic is replaced by nyl chloride 19.1 m/(21.7 g).

Following the procedure described in Example 3, but using 0.2 mol), N-ethoxycarbonyl-1,2-dihydropyridine is obtained, which is then further treated as described in Example 4. The title compound is obtained.

Suictor: 6.56 and 6.63 (m, 5H and 6H); 3.08 ppm (m, 4H).

Yield: 11.8.9 (24.6%).

Example 7 N-benzyloxycal? Starting from 0.2 mole of nyl-4-ethyl-7-ethoxycarzanyl-2-azabicyclo[2,2,2]oct-5-ene 3-ethyl-pyridine and following the procedure described in Example 1, approximately 35 to 40 Il of 1,2-dihydro-3-ethyl-pyridine was obtained which was then converted into o, ig
of hydroquinone in 150 mg of methyl acrylate. The reaction mixture was heated for 10 days, i.e. λmlL of UV radiation! == Boil until the 305 nm peak (characteristic of the dihydropyridine peak) disappears. The reaction mixture was evaporated in vacuo at 40-50 °C and the oily residue was then evaporated in Kieseldal 60 (0,063-0.2 va) using a 10:1 mixture of benzene and acetone as eluent.
n) Separation by column chromatography treatment.

Yield: 24-25 g (0,072-0.075 mol),
38-40 chi.

t, l', c, Kieserg #60 PF254 r Eluent: 10:1 benzene/acetone, developed in iodine vapor or with 254 nm UV light: R, = 0.
75° IR (film) an-”: 1680 acid amide carbinyl, 1820 ester carbinyl 1470 phenyl.

Example 8 2-penzyloxycasimenyl-5-exo-bromo-
6-Nindohydroxy-7-exo-chloro-2-azabicyclo(2,2,2)octane-7-nindocargenic acid γ-lactone Following the procedure described in Example 3, 17.0.9 (0,084
65 mol) of N-benzyloxycar? Nyl-1,2-
Dihydropyridine is obtained. The product was dissolved in 150 d of anhydrous acetonitrile and then 18 mg (0,187 mol)
Freshly prepared α-chloroacrylic acid chestnut P and 0
．． Add 2.9 parts of hydroquinone. The reaction mixture is stirred at room temperature overnight. The end of the reaction is λma! =305nm
Beak (this is a property of 1,2-dihydro compounds)
is controlled using the UV spectrum while monitoring its disappearance.

To the homogeneous acetonitrile solution, 30-distilled water is added and the mixture is stirred for 30 minutes. The organic phase is extracted with 150 rnt portions of saturated potassium bicarbonate solution, which solution contains ammonium chloride in a solution of 100 m
Contains 11. - The combined aqueous phase is dichloromethane 3
Extract at 0- and then remove the organic phase from the aqueous phase under vacuum.

Approximately 2 ml of bromine is added dropwise to the solvent-free aqueous phase with stirring until the yellow solution disappears and precipitation stops. Excess bromine in the solution is bound by adding an aqueous solution of 2-3 g of sodium thiosulfate. Filter the precipitate,
Dissolve in 50 mj of ethanol and then combine the bromine present in the precipitate by adding a small amount of aqueous sodium thiosulfate solution. The product crystallizes from the solution on cooling.

Yield: Crystalline powder (15% > 6.010.015 mol) Melting point: 130-131°C t, 1. c, (Kieselgur G, eluent: 10:1
Benzene/acetone, development: iodine vapor): R, = 0.
65 IR spectrum: KBr cm C=0,1800 C
= 01720, mono-substituted phenyl 1405 and 705 NMR spectroscopy (CDCl2) ppm: 7.38
(Ar-H5); 5.25 (benzyl-CH2-, s
): 5.1-4.8 (H1' and H16); 4.2 (
Hl” d): (4,1(H,d):4.1 and 3.5(Hl,d):2
．． 5 (H, +H2).

Example 9 2-benzyloxycardani-4-ethyl-5-exo-bromo-6-nindohydroxy-7-exochloro-2-azobiciclo[:2.2.2]octane-2
-Endo-carboxylic acid r-lactone 9N-benzyloxycal obtained as described in Example 1 is nyl-1,2-dihydro-3-ethyl-pyridine 40.61! (0.2 mol)
2-Chloroacrylic acid chloride was prepared freshly by dissolving it in 100rnt of anhydrous acetonitrile. i
' (0,24-1 nyl) and 0.2 g of hydroquinone are added to the solution. While protecting the reaction mixture from light,
Stir for days. The progress of the reaction was monitored by UV spectrum analysis. The reaction ends when the peak λmax=305 nm corresponding to 1,2-dihydro-3-ethylhyridine disappears. The homogeneous acetonitrile solution is cooled to 10° C., then 100 ml of distilled water are added with stirring and the mixture is stirred for 2 hours.

Separate the aqueous and organic phases. The organic phase was cooled to 10° C. and then 40 d of 25 g potassium bicarbonate solution was added to pi-18
Drip until . The aqueous phase is separated from the acetonitrile phase and extracted twice with dichloromethane LOO+nt. Traces of solvent are then removed in vacuo on a water bath at 30-35°C. Take a bath! In the aqueous phase maintained at 1140°C,
Bromine is added dropwise with continuous stirring until the solution becomes yellow in color. The precipitated yellow solid is dissolved by dropwise addition of 100 d of dichloromethane, and the system is then extracted with 10% aqueous sodium thiosulfate until the solution becomes colorless.

The dichloromethane phase is separated, dried over magnesium sulphate, filtered and evaporated in vacuo.

Yield: oil 16-171i+, which contains 4 t, 1.
c. Give a spot.

t, +, c, (Kieselglu 60. Eluent: 10=1 mixture of benzene and acetone, development: in iodine vapor) The dual target substance is obtained with R, = 0.53.

Using a 10:1 mixture of benzene and acetone as eluent,
By chromatographic treatment of the crude product in 0.30 times the amount of m), the initial oily substance can be isolated as the target substance. R, = 0.22, containing a carbunyl group at the equatorial position? Furthermore, based on the IR spectrum, other spots correspond to various caldic acid derivatives.

Yield: l, 6-1.7.9 (0,00374-0.0
042 mol).

Appearance: Yellowish oil IR sictor (film) rrn-1: C=Q lactone 1820, C=o benzyloxycarginyl, 172
0. Monosubstituted phenyl 1405 and 705° NMR spectrum (CDCl2) ppm: 7.38
(Ar-H5); 5.25 (benzyl-CH2,)
; 5.1-4.8 (Hll and H,'); 4.2
(I(,5,d) :l,3(ethyl triplet)
.

Example 10 2-penzyloxycarbinyl-twochlor-7-caldexamido-2-azabicyclo(2,2,2:]]oct-5-ene, 2 g (0,01 mol) of N-benzyloxycarbinyl-7 -chloro-7-cyano-2-azobicyclo(
2,2,2) Oct-5-ene is dissolved in 10 m/dimethyl sulfoxide, and then to this solution is added 0.45 g (0,025 mol) of water obtained at 100°C and 1.4 # of potassium hydroxide. (0.025 mol) is added with vigorous stirring. The reaction is monitored by thin layer chromatography. The starting material is consumed in about 3 hours. The reaction mixture is diluted with 25 volumes of distilled water while stirring vigorously. The precipitated oil becomes a well filterable precipitate within a few hours. The precipitate is filtered off and washed twice with distilled water. After drying, the precipitate was recrystallized from 3-ethanol to yield 1.41 o, oo 43 mol of the title compound.

43 Ch) is obtained.

Appearance: white crystals Melting point: 134-137 °C t, l, c, (Kiesseldal 60F254 plate, eluent: 8:4:2 mixture of benzene, chloroform and hyethanol; development: in iodine vapor or 254 nm UV light) 2R,=0.6
According to 4° elemental analysis, the product contains chlorine, which is bound covalently.

IR Suji) Le (KBr) tyn-': 3400-3
30ONH.

2870-2900CI (, 1680-1660 acid amide.

Odorisu 4 liters (CDCl2) ppm: 7.3 (s
ArH5): 6.4 (m,'H,'+)11')
;6.0 (mNH2) can be replaced with heavy water. 5.2
(Benzyl CH2); 5. O(m H1').

Example I N-pennoloxycarbonyl-4-ethyl-7-medoxycarbonyl-2-azabicyclo(2,2,23oct-5-ene 1,5# obtained according to Example 1 (0,004 mol) 2
-benzyloxycarbonyl-4-ethyl-7-chloro-7-medoxycargenyl-2-azabicyclo[2,2
. The reaction mixture is refluxed for an hour under an argon atmosphere. When the entire amount of starting material is consumed, the reaction mixture is cooled to room temperature, the zinc is filtered off, the mother liquor is evaporated to give an oil, and then the zinc is dissolved in water 2
Wash with 0ml and 20rnt of chloroform. The aqueous phase is added to the oil and the resulting mixture is then extracted with 30 d portions of chloroform. - The combined chloroform solution is dried over magnesium sulphate, filtered and evaporated.

Yield: 1.2JB0.0036mol) 90t, 1. c.
, (Kiesseldal 60PF254; Eluent: 10:
1 benzene/acetone; a open: in iodine vapor or 254
nm UV light): IR spectrum/L'crn-': 1470:1680
Acid amidocarnyl; 1720 estercarnyl.

Halogen content: None Example 12 7-chloro-7-medoxycardenyl-2-azabicyclo[:2.2.2]oct-5-ene hydrobromide 10 g (0.03 mol) of 7-chloride obtained according to Example 3 -Chlor-7-
Medoxycarzanil-2-azabicyclo[:2.2.2
] Oct-5-ene is dissolved in a mixture of 60rnt of glacial acetic acid and 30ml of 4-5N hydrogen bromide solution dissolved in glacial acetic acid. The mixture is left at room temperature for 10 minutes and then evaporated. The evaporation residue was dissolved in 5 ml of acetone and then 3
00- ether is added to the solution. The precipitated crystalline material is filtered off.

Yield: 8g (94%) Melting point: 188°C IR spectrum: 1720cr++:r-ste#C=
ONMR spectrum: 3.75 ppm (s −0
CR, ): 6.2-6.5 ppm (Olefin H
-s).

Example 13 7-chloro-7-diatu-2-azabicyclo[2,2,
2] Oct-5-ene hydrogen bromide 5.0g (0,0165
mole) of N-benzyloxycarvinyl-7-chloro-
7-dia/-2-7 debicyclo(2,2,2)ophtolu-5-ene is dissolved in a mixture of glacial acetic acid 30 and 4-5N glacial acetic acid/hydrogen bromide mixture 15-. The reaction mixture is left at room temperature for 10 minutes and then evaporated. The evaporation residue is crystallized from acetone.

Yield: 2, Og (0,0081 mol) 49% Melting point: 22
4-226℃.

IR spectrum: 2220 cm C2NNMR spectrum (DMSO, d6): 4.5 ppm (d
H1′); 5.8-6.6 (m H5+ H6).

Example 14 4-ethyl-7-chloro-7-medoxycardenyl-2
-Azabicyclo(:2.2.2) oct-5-ene hydrochloride 16g (0,044 mol) N-benzyloxycar♂
7-10-7-me)oxycarbonyl-2-azabicyclo(2,2,2)oct-5-ene, 57mj
of glacial acetic acid and a 5N solution of hydrogen bromide in glacial acetic acid 114
- dissolve in a mixture of The reaction mixture was heated to 0.5-1 at room temperature.
Leave it for a while. The reaction process is monitored by thin layer chromatography. The mixture is then evaporated in vacuo in a water bath at 40-50°C. The oily product obtained is triturated with ether and decanted. The residual oil was purified using Kieselgl 60 (0,0063-0.2+) using a 8:4:2 mixture of benzene, chloroform and ethanol as eluent.
The column is subjected to the cyclomography treatment of m).

The products obtained at R, = 0.1 and R, = 0.2, respectively, are collected. The two products differ in the configuration of the caldemethoxy group.

Yield near 2g (53%) t, 1. c, (Kiesseldal 60F254; Eluent:
10:1 benzene/acetone; developed in iodine vapor):
R, = 0.6° Under the same conditions except that the eluent was a 8:4:2 mixture of benzene, chloroform and hyethanol: R
, = 0.1 and 0.2° Example 15 4-ethyl-7-chloro-7-cyano-2-azobicyclo(2,2,2)oct-5-enebromochloride N -benzyloxycal is 4-ethyl~7-chloro-7-dia-2-azobicyclo(2,2,2'loct-5-
Ene 11-1 is dissolved in a mixture of 2 tnt of glacial acetic acid and 0.1-t of a 5.3N solution of hydrogen bromide in glacial acetic acid. The mixture is left at room temperature for 0.5 hour with exclusion of moisture. The mixture was evaporated in vacuo on a 40°C water bath, then acetone 2
Evaporate 0d and 10m of methanol twice. In addition to the target product, the evaporation residue also contains the corresponding acid obtained by hydrolysis of the cyano group. The two products were mixed with benzene, chloroform and ethanol as eluents.
:4:2 mixture, Kieselgur 60 (0,06
3~Q, 2wn) column.

Yield: 0.1 g (0,00035 mol, 1
2%).

t, t, c, (Kieserglu 60F254"eluent; benzene, chloroform and hyethanol 8:4:2 mixture): R7 acid = 0.14; Rf nitrile = 0.44° IR spectrum (KBr) cm-": 3330N
H,2300C=NO NMR spectrum #(CDC45ppm: 6.1 (
m Hl + H1)*4.2 (d, Hl); t
2 (tethylCH,).

Example 16 Fuprom-7-methoxycargenyl-2-azobicyclo(: 2.2.2.1 oct-5-ene hydrochloride N-benzyloxycal-7-brom-7-medoxycar-2- Azabicyclo[2,2,2]octo-5-
en8. Og is dissolved in 40 d of dichloromethane and the resulting solution is then saturated with hydrogen bromide gas while cooling. After saturation, the mixture is further left in the oven and then evaporated to give an oily residue, which is then crystallized from acetone.

Yield: 4.019 (0,0125 mol, 60 ti).

t, 1. c, (Kiesseldal 60F254; Eluent:
Benzene, chloroform and ethanol 8:4:2 mixture; developed in iodine vapor): R, = 0.55°IR
Spectrum (KBr) m-': 1740 C=O;
1250 0Cf (3° or less White Example 17 Fukroru-7-Cal?xamide-2-azabicyclo [
2,2,2) Oct-5-ene bromate N-benzyloxycal? Nyl-7-chloro-7-caldexamide-2-
azobicyclo[2,2,2]oct-5-ene 2.01
0.0075 mol) in 4 rnl of glacial acetic acid and then 3d of a 5.6N solution of hydrogen bromide in glacial acetic acid are added. After standing for 0.5 hour, the solution is evaporated in vacuo on a 40-50°C water bath. The oily residue is evaporated off with 4o-methanol. The oily residue is crystallized from a 2:1 mixture of acetone and ethanol.

Yield: 1.510.0055 mol, 74%) Appearance: Crystalline white powder Melting point: 210-253°C t, 1. c, (Keymolglu 60F254; eluent: benzene, chloroform and hyethanol 8:4:2 mixture; developed in iodine vapor ■Rf = 0.
1゜IR spectrum (KBr) m-': 3400-3
30 ONH: 2900-2800CI (2,1680
Amide 1,1580 amide ■.

NMR spectrum (CDC15) ppm (from base): 6.5 (m f(,'+H,') 13.8-3.
9 (mlH,').

Example 18 6-methoxycal is nyl-2-azabicyclo[2,2,
2] Octane hydrochloride N -benzyloxycar♂yl-7-chloro-7-methoxycaryl-2-azabicycloC2,2,2]oct-5-ene and 10.1,9[, dichloromethane 40- and Dissolve in a mixture of methanol 60me. Radium catalyst supported on charcoal 1.0. F, methanol 2
A clear solution of the raw material to be prehydrogenated and then hydrogenated in a closed system is added in a closed system. Hydrogen is bubbled into the solution for about 8 hours while stirring vigorously. The course of the reaction can be monitored by measuring the carbon dioxide content of the gas blown into the solution. a. Monitor the situation.

R7 starting material 2 0.9-1.0 R, chloro ester: 0.1 Rf ester: 0.2 Once the hydrogenation is complete, filter the catalyst, wash with a small amount of methanol, remove the mother liquor with methanolic hydrochloric acid Adjust to 2 with solution and then evaporate the mixture.

50° of acetone is added to the residue and then evaporated to about half its volume. Crystallization of the product is very slow, requiring about a week in refrigeration. The product is then filtered off and washed twice with cold acetone.

Yield: 4.8 g (0.0235 mol, 78%) Melting point: 139-141°C t, Lc, (Kiesel 60F254; Eluent: 3 benzene/acetone; developed in iodine vapor) 2R7
Starting Material>Rf product.

IR spectrum (KBr): 1720=C=0.

1250 cnn-OCH3H-NMR (CDC131
Base) 4.05 (m,, IH.

H-1); 3.65 (8,3H,0CH30CH
3).

Example 19 5-exoprom-6-endo-hydroxy-7-exo-chloro-2-azobicyclo(:2.2.2)octane-7-nindocarboxylic acid γ-lactone hydrochloride 2-pennoloxycarbonyl -5-exo-brome-
6-Nindohydroxy-7-exochloro-2-azabicyclo(2,2,2)octane-7-nindocaldenic acid γ-lactone 6,011 (OX) (15 mol) is dissolved in chloroform 150-. The solution is cooled to 0°C and saturated with hydrogen bromide gas for about 15 minutes. When the hydrogen bromide solution is allowed to stand overnight, the desired product precipitates out as a white crystalline material. It is filtered off, washed twice with 10-chloroform and dried.

Yield: 3.1 g (0,009 mol, 60%) Melting point = 20
7-209 °C IR spectrum (KBr) cm-': 1800 C=
O; 3450 N-H Traction Spect # (CDC23) ppm: 4.9 (
2xd H,'); 4.24 (broad dH4); 3.
6 (2xd H1'): 3.55 and 3.12 (f
(2AB multiplet).

Example 20 4-ethyl-5-endo-7'' rom-6-nindohydroxy-7-exochloro-2-azobicyclo[2,
2,2] Octane-7-nindocargonic acid γ-lactone hydrochloride Crude 4-ethyl-5-exoprom-6-endo-hydroxy-7-exo-chloro-obtained according to Example 9
2-benzyloxycarzanyl[2,2,2')octane-7-nindocargenic acid γ-lactane 16,0g was dissolved in 100% of dichloromethane, and the resulting solution was diluted with hydrogen bromide gas for 30%. Saturate while cooling for a minute. The reaction mixture is left overnight. Thereafter, it is evaporated in vacuo on a water bath at 40° C., and 100 ml of acetone is further evaporated from the solution four times.

The evaporation residue was purified with benzene and acetone as eluent.
Chromatography is performed using a mixture of:1 and 30 times the amount of Kieseldal. The product is then crystallized from absolute ethanol.

Yield: 2.2-3.0.9° Appearance: White crystalline powder IR spectrum (KBr) cm-': C=0 1
820: N-H345O NMR spectrum pv (CDCl2 *base) ppm
: 4.4 (dH,); 3.45 (triple ring, H1
).

3.3 (m H2') ': 2.4 (m H2)
.

Example 21 6-chloro-6-methoxycargenyl-2-azabicyclo[2,2.2]octane hydrobromate 7-chloro-7-methoxycardenyl-2-azabicyclo[:2.2.2]oct-5- 8.5.9 (0.03 mol) of enebromate are dissolved in 85rnt of methanol. 1 supported on charcoal
0.85 gk of 0% palladium catalyst, prehydrogenated in 15 d of methanol, and then a clear solution of the starting material to be hydrogenated is added in a closed system. The hydrogenation is carried out in a closed system and the course of the reaction is monitored by the consumption of hydrogen. The reaction is complete when the theoretical amount of hydrogen has been absorbed. If the reaction does not finish in a timely manner, allow the reaction to proceed further;
Replaces chlorine with hydrogen. All of the catalyst is filtered off and the solution is evaporated. A crystalline material is obtained which is triturated with about 20° C. of acetone and left overnight in the refrigerator. The next day, filter the precipitate and
Pulp twice with 54 parts of cold acetone and then dry.

Yield near! i+ (0,0244 mol, 82 mol) Melting point:
181-183°C Example 22 2-(n-butyl)-7-chloro-7-methoxycar?
9.6 g (3
4.0 mmol), n-butyl bromide 4.78. P(34
, 8 mmol) and 13.6 g (13
4.5 mmol) in 100 ml of methanol! dissolve in Leave the solution for a total of two days. The course of the reaction was monitored by thin layer chromatography using a 8:4:2 mixture of benzene, chloroform and ethanol as the solution and using a KeyKurglu 60F254 plate. Development is carried out in iodine vapor. Rf product: 0.9; R, starting material (base) = 0.5°. The reaction mixture is evaporated and the evaporation residue is triturated with approx. 200° of n-hexane. The precipitated triethylamine hydrochloride and bromide salts are each filtered off from the hexane solution and then washed with hexane. Evaporate the hexane mother liquor. The evaporation residue is separated into its components by column chromatography, carried out on a Kiesel 60 (0,063-0,2 ym) column and using benzene, chloroform and ethanol 8:4:2 as eluent. A mixture was used.

Yield: 2.1.9 (24.0 Ti), Oil IR spectrum (film): 1720 crn-' Ester C==
O NMR sample (CDCl2) ppm:
6.2 and 6,5 (m Hl"+H1'); 3.85
(d, F5”); 3.7 (a-0CH3).

Example 23 N-(n-butyl)-7-chloro-7-diatu-2-
Azabicyclo(2,2,2:)oct-5-ene7-chloro-7-cyano-2-azabicycloC2,2,2:]
] Octo-5-ene bromochloride 1.0, anhydrous methanol 5
ml and then 0.5.9 g of triethylamine followed by 0.5 g (3.65 mmol) of n-butyl bromide.
Add to the solution. The progress of the reaction is determined by Kieselguru 60
Monitored by thin layer chromatography using F254 plates and elution with a 8:4:2 mixture of benzene, chloroform and hethanol. R, starting material (base): 0.53: Rf product: 0.95° (development was carried out in iodine vapor or with 254 nm UV light). The reaction product was evaporated in vacuo and then chromatographed on a 30-fold volume of Kieselgl 60 (0.063-0.2 tone) column using a 8:4:2 mixture of benzene, chloroform and ethanol for elution. .

Yield: 0.342 (0,00152 mol), 38 tit.
1. c, (Keyilglu 60F254; eluent: benzene, chloroform and ethanol 8:4:2 mixture; developed in 254 nm UV light or iodine vapor): R, = 0.95° NMR spectrum (CDC2,) ppm: 6.7 (m, H75+
H1'):4. O(d, df(,'); 3.5 (d,
dH,').

Example 24 N-(2-(3'-indolyl)-ethyl]-7-chloro-7-methoxycargonyl-2-azabicyclo[2
,2,2:]]oct-5-ene 7-chloro-7 medoxycarpinyl-2-azabicyclo(2,2,2]oct-5-ene hydrochloride 6.0 g (21,2 mmol), bromotryptophan 6.0.9 (27 mmol) and triethylamine 25g (18.0 g, 0.18 mol),
Anhydrous methanol 80rn1. dissolve in Leave the solution at room temperature for one day. The course of the reaction was carried out using a 10:2 mixture of toluene and ethyl acetate and Kieseldal 60 as eluent.
The plate is monitored by thin-layer chromatography and then subjected to hydroxide-black air development. R7 Product 20.5° The reaction mixture is evaporated in vacuo. 300 d of ethyl acetate are added to the evaporation residue and the precipitated solid triethylamine hydrochloride is then filtered off. Evaporate the mother liquor.

The evaporation residue obtained (approximately 711 oily product) is crystallized from a mixture of 50 m ethyl acetate and 2-3 m of n-hexane. The mother liquor of the product was purified by Kiesergl 6 using a 10:1 mixture of toluene and ethyl acetate as eluent.
0 (0.063 to 0.2 .mu.) and the product is then crystallized from a mixture of n-hexane and ethyl acetate as described above.

Yield: 3.5F (48.6%) Melting point: 128-130℃ IR hard KBr: 1720crn Nisual C=0.34006n Indole-H spectrum, ppm: 7.9 (Indole N
-f();7.6(m aromatic f():6.2,6.5
(m+H1+H7); 3.8 (1-0CH5)
.

Example 25 N-[:2-(3'-indolyl)-ethyl]-7-chloro-7-dia-2-azabicyclo[2,2,2]oct-5-enbromotryptophan 0.9.9% in anhydrous acetonitrile Then 7-chloro-cyano-2-azabicyclo(2,2,2)oct-5-ene hydrochloride 1.
0 g (0,00403 mol) and 2.4 nIt of anhydrous triethylamine are added to the solution. The obtained homogeneous solution was
Stir for 3 days, excluding light and moisture. The course of the reaction is monitored by thin layer chromatography. The Rf tryptophan bromide is 0.86 and the AmR2 product is 0.76 using a Kieselglu 60F2.4 plate using a 10:1 mixture of benzene and acetone as eluent. The reaction product is evaporated in vacuo on a water bath at 30-40°C. The evaporation residue is dissolved in ether 15 and then extracted twice with 5 ml of aqueous ammonia (pi=10).

The ether phase is dried over magnesium sulphate and then evaporated in vacuo. The oily product obtained is crystallized from 3 ml of methanol.

Yield: 0.71 g (0,002324 mol), 5
5% melting point: 126-128°C t, 1. c, (Kieselglu 60F254; Eluent:
10:1 benzene/acetone development: (in 254 nm UV light or iodine vapor) R, = 0.7
6 TRx-e (KBr) cm-': 2300
C==N.

3300 Indole NH NMR Spectrum (CDCts) I) Pm: 3.
8 (d*Hs) e6.2-6.8(rn H1+H
,).

7.05-7.7(m Ar H+India-Jl/H1
')c Example 26 N-(2-(3'-indolyl)-ethyl-6-chloro-6-medoxycarnyl-2-azabicyclo(2,
2,2) Octane 3-chloro-6-methoxycargonyl-2-azobicyclo[:2.2.2]octane hydrochloride 3.84F (0,0
13 mol), bromotricytophane 3.05I and triethylamine 5.551 (0.os2 mol, 7.6 m
), dissolved in 35 g of absolute methanol, and then the solution is left at room temperature for three days. The reaction mixture is evaporated and a mixture of 70+d benzene and 35 mj water is then added to the evaporation residue. The organic phase is separated and then washed twice with 15 portions of water. -The combined aqueous phases are extracted with benzene 15-. - The combined benzene phases are dried with magnesium sulfate, decolorized with charcoal and evaporated in vacuo. From the evaporation residue, 25 g of ethanol is removed by evaporation and the residual solid cloud is then crystallized from 3 mt of ethanol. The mother liquor is separated and the residue is then crystallized from iteproΔnol.

Yield: 1.5 g (0,0043 mol), 33 ti.

Example 27 N-(2-(3'-indolyl)-ethyl]-7-chloro-6-hydroxy-5-bromo-2-azobiccyclo(2,2,2)octane-7-calanoic acid γ-lactone 7-Rio-6-hydroxy-5-bromo-2-azobicyclo(2,2,2)octane-7-calanoic acid γ-lactone hydrochloride (0.689 JiN: 0.0027 mol) was added to 3 mol of water. - and then adjust the pH to 8 to 9 with a saturated aqueous ammonium hydroxide solution. Extract with 5 portions of aqueous dichloromethane and then dry the combined dichloromethane phases over magnesium sulfate. The mixture is then evaporated in vacuo on a water bath at 30-40°C. The oil obtained is dissolved in anhydrous chloroform 6- and then bromotricytophan (0.66910.00298 mol) is added. The reaction mixture is heated on an oil bath at 100-110°C for 1 hour. The concentrated reaction mixture was diluted with 5 rn of dichloromethane.
! and 2 d of water to dissolve. Extract the organic phase with 2 tablespoons of water each. The dichloromethane phase is dried over magnesium sulphate and then evaporated in vacuo.

Yield: 0.34.9 (0,000864 mol), 3
5%.

t, 1. c, (Kieselgur 69F2.4; 10:1
Benzene/acetone; developed in 254 nm UV light or iodine vapor: R, = 0.7 Melting point: 134-147°C Example 28 N-(2-(3'-indolyl)-ethyl]-4-ethyl-7 -chloro-7-methoxycardenyl-2-azobicyclo[2,2,2]oct-5-ene 4-ethyl-
7-chloro-7-methoxycarl? Nilu-2-azabicyclo(2,2,2)oct-5-ene 10.3g (0,
033 mol), bromotricytophane 7.4. lO,0
33 mol) and 19 ml of triethylamine are dissolved in 80 ml of absolute methanol.

The reaction was carried out at room temperature and monitored by thin layer chromatography (Kiesel R60F254 plate) using a 10:1 mixture of benzene and acetone as eluent until complete consumption of tryptophan bromide, resulting in a new compound. is benzene, chloroform and ethanol 8:4
:Can be detected in a mixture of the two. The reaction mixture is evaporated in vacuo. 100 ml of water is added to the residual oil, and the resulting mixture is then extracted with 100 ml portions of benzene. - The combined benzene phases are dried over magnesium sulphate, filtered and evaporated. t, 1. c. If the reaction mixture does not contain decomposition products, the desired product is crystallized from 96 g of ethanol. If the reaction mixture contains by-products due to decomposition, the crude product is purified by column chromatography.

Yield: 3.8 g (1.0 gmol) 31 t, I,
c, (+ (-Cell l'le 60 F254: Eluent:
10:1 mixture of benzene and acetone and 8:4:2 mixture of benzene, chloroform and hyethanol; development: 254 nm UV light or iodine vapor): R,: 0.75° IR spectrum, $, 3300 India- /I/NH1
1720 ester C=O0 NMR spectrum) #(CDCl2) ppm: 6.2
-6.8(mH,+H1"), 7.05-7.7(
mAr+indole H, 2).

3.8 (dH4).

Example 29 N-(2-(3'-indolyl)-ethyl-4-ethyl-5-bromo-6-hydroxy-7-chloro-2-azabicyclo[:2.2.21octane-7-calanoic acid γ- Lactone 4-ethyl-5-f rom-6-hydroxy-7-chloro-2-azabicyclo[2,2,2)octane-7-cal? γ-lactone hydrochloride 0.26. ! i+(0,00
09849 mol) is dissolved in methanol 2d. To this solution was added 0.15 d (0,143 mol) of triethylamine and 0.22 g (0,0009 mol) of bromotritophane.
8 mol) is added. The reaction mixture was placed on a 60°C oil bath.
Stir for 1 day while protected from light. The progress of the reaction was monitored by thin layer chromatography (Kieselglu 60 plate, 1
0:1 benzene/acetone; developed with iodine vapor). When the reaction is completed, the R,=0.76 peak corresponding to bromotryptophan disappears, and then a new peak corresponding to the target compound appears at R,=0.5. The reaction mixture is evaporated under vacuum on a water bath at 40-45°C.

The evaporation residue was extracted with Pe/Zene and acetone 10 as eluent.
:1 mixture, Kieserrle 60 (0,063 ~
Chromatography is carried out using 30 times the volume of 0.2■).

Yield: 0.15 g (0,0003435 mol), 3
4.8%t, 1. c, (Kiesel r60F254;
10:1 benzene/acetone; developed with iodine vapor):R
f=0.5 IR (film) m-': 3300 indole NH
: 1820C=0 (KBr) 3450 indole NH; 1820-O NMR spectrum (CDC45) ppm: 7.05-
7.7 (m, Ar H+India-/I/H1) +4.
4 (d H,”); 3.45 (triple ring H,')
;3.3 (m, H25) : 2.4 (m H2
8).

NMR spectrum (CDCl2. base) ppm:
4.4 (d, H1'); 3.45 (triple ring H11
); 3.3 (m H2') : 2.4 (m H2
8).

Example 3 O N-((3'-indolyl)-acetyl]-7-chloro-7-methoxycarbinyl-2-azabicyclo[:2
．． 2.2] oct-5-eneindolyl-3-acetic acid 5.811 (0.03 mol) and triethylamine 4.6y (3,31'< 0.03
3 mol) is dissolved in trimethylformamide 97-.

The solution is cooled to -5 DEG C. to -10 DEG C. and then 4.1 d (4.1 g, 0.034 mol) of chlorpivalic acid is added dropwise at the above temperature. After stirring for 20 minutes, a thick suspension is obtained.

To this suspension was added 8.0 I00284 mol of 7-chloro-7-methoxycargonyl-2-azobiccyclo[2,2,2:]]octo-5-ene hydrochloride) and 4.0 mol of triethylamine dissolved in 97 ml of dimethylformamide. 6m1
(3,311,0033 mol) is added at a temperature of -5°C to 0°C. The reaction mixture is then allowed to warm to room temperature and stirred for an additional hour. The precipitated triethylamine hydrochloride and bromide were each filtered and then dimethylformamide 5
Wash with ml. Evaporate the mother liquor under vacuum. The evaporation residue is dissolved in 400 ml of ether acetate, washed twice with 40 ml of water and dried over magnesium sulfate. The ethyl acetate solution is evaporated and the precipitated crystalline product is then filtered off.

Yield: 8.5g. The crude product was dissolved in chloroform at 250 m
1 and 6'Oml of methanol and then evaporate the solution. The precipitated crystalline product is filtered off and washed with 10-chloroform. Yield: 8.1 g (0.0226 mol), 68 ml.

Melting point = 201-202°C IR spectrum (KBr) cm-”: Ester C
=01720, acid amide C=0 164ONMR spectrum: 7.0-7.79pm: indole aromatic; 5.8 and 6.4ppm: m(H5+H6) 3.75 ppm (s-OCH3
).

Mass spectrum/l/mlz: M=358 + 32
2 + 301 + 299.238, 157, 130, 1
21゜119.117,103,93,91゜81.8
0.77 Example 31 N-[:(3'-indolyl)]-]acetyl]-7-
Chlorou 7-Dia2 2 Azabicyclo (2,2,2:]
] Octo-5-ene-chloro-cyano-2-azabicyclo(2,2,2)
Oct-5-ene hydrogen bromide8. Ol (0,'032
The title compound is obtained by following the procedure described in Example 30, but starting from %l).

Yield: 4.65 g (0,0143 mol) 44.6% Melting point: 176°C IR spectrum (IBr): Acid amine P C = 01640
cIn.

Cyano 2230 cm-1 Gotan spectrum: 7.0-7.7 ppm, indole aromatic.

6.6 m (H5+H6) Mass spectrum m/z: M=325.389.238
゜158.157, 130, 121, 117゜116,
．． 103,102,93,81°80.77°t,+,c, (Kiesel 60F254 plate, eluent: 10:1 mixture of chloroform and methanol, developed in 254 nm UV light and iodine vapor):
R, = 0.7 Example 32 N-[(3'-indolyl)-acetyl-6-chloro-6-medoxycarvinyl-2-azabicyclo(2,2
, 2:) octane 3-indolyl-acetic acid 7.11,) ethylamine 4.
2 g (0.04 mol, 5.75 m) are dissolved in anhydrous dimethylformamide 120-. The solution was heated to -5°C to -
Cool to a temperature of 10° C. and then add pivalic acid chloride 4.8.
9 (0.04 mol, 4.9 g) was added dropwise at the same temperature. After stirring for 20 minutes, a thick suspension was obtained, to which was added 6-chloro-6-methoxycal? Niru 2-AzabicycloC2,2
, 2] A solution of 11.4 g (0.04 mol) of octane bromide and 4.2 g (0.04 mol) of triethylamine dissolved in 120-dimethylformamide is added at a temperature between 0.degree. and 0.degree. After the addition is complete, the mixture is stirred for a further 1 hour at room temperature. The precipitated solid, which is triethylamine hydrochloride or bromide, is filtered off and washed with a small amount of dimethylformamide. The mother liquor is vacuumed at 10-20 torr.
Evaporate on a 60°C water bath. To the evaporation residue, 400 g of ethyl acetate are added, and the mixture is then diluted twice with 40 g of water.
60ml of 5% sodium bicarbonate solution and finally 20ml
The mixture is washed with 60 ml of sodium chloride solution, dried over magnesium sulfate and evaporated. The evaporation residue is crystallized from ethanol 300-.

Yield: 9.3.10.026 mol), 65% melting point = 19
5-196℃.

Example 33 N-[(3'-indolyl)-acetyl]-7-promo-7-methoxyl is
2,2:]] Octo-5-ene 3-indolyl acetic acid 2.2 g (0,0126 mol) are dissolved in anhydrous dimethylformamide 30-. 1.29 of triethylamine was added to the solution, which was then heated to -5°C.
Cool to -10°C. At this temperature, 1.69 (0.01'26 mol) of bivalylic acid chloride are added dropwise with vigorous stirring. Triethylamine hydrochloride immediately precipitates from solution. After stirring for 20 minutes, 7-promo-7-methoxyal was converted to nyl-2-azabicyclo[2,2,2:]]octo5
-enebromate 4 (1 (0,0126 mol)) and triethylamine 1. dissolved in dimethylformamide 20me.
Add solution of 2Ii. The mixture is stirred for a further 1 hour at room temperature and then the precipitated triethylamine hydrochloride or bromo salt is filtered off. Evaporate the mother liquor in vacuo on an oil bath at 60°C. The evaporation residue is dissolved in 300 rnt of dichloromethane and washed with 100+t of water. The dichloromethane phase is dried over magnesium sulphate and then evaporated in vacuo.

The evaporation residue is crystallized from acetone.

Yield: 2.0I0.005mol) 40t, 1. c, (
Keymolglu 60F254: Eluent: benzene, chloroform and ethanol 8:4:2 mixture, development: 254 nm UV light or violet-black air) Rf = 0.85 IR spectrum (KB
r) cm-': 3250 NH.

1720 Ester C=0. 162ON-C=0
Near, 7-7.3 indole aromatic, 6.6m (H15
+ H4') 15.0 (m H1').

Example 34 A preliminary test to investigate the pharmacological effects of the compound obtained according to the present invention and a sex test were conducted on rats.

The LD5o and ED5o of the compound of Example 24 were found to be s 30 ny/kg (1-p-') and 8 Tn9/lv (1,p,) in mice, respectively. ED5
o is G6 Takaatay and J, Fuasz
(Acta m1crobial・Acad, Sc
i, Hung, 3 +105 +1955) or J
, Cotney (Agents and Acti
ons, 10 +48.1980), etc.

Example 35 Regarding the use of intermediates, the compound of Example 3o is CS.

5. The method of Zantay et al. (Tetrdhedron L
etters.

24.5539.1983) by (±)-oxo-2
It can be converted to 0-deethylcatharanthine, which is further converted to R,J
, Sundberg and J, D. Bloon's method (J.

Org, Chem 45, 3382.1980).

When 2o-deethyl anhydropine brostin (see Gusritte's literature below) with antitumor activity is obtained, the latter can be obtained by the method of F. Gueritte et al.
J. Org. Chem. 46.5393.1981).

Patent Applicant Richterketeomba Vinepi÷ti Jarruaturu, Chi.

Patent application agent Akira Aoki Patent attorney Kazuyuki Nishidate Patent attorney Yukio Uchida Patent attorney Akira Yamaguchi Patent attorney Masaya Nishiyama Continuation of page 1 o Inventor Gielji Hayos Hanga 9 @ Inventor Chaba Susantai Hanga @ Inventor Tipol Kebe Hanga0 Inventor Gielji Huekete Hanga@Inventor
Gabor Mezieli Hanga @ Inventor Tipol Aci Hanga

Claims (1)

[Scope of Claims] 1. The following formula I: Phenyl alkoxycarous group having 1 to 4 carbon atoms in the xy moiety is nyl, C4-6 alkyl, 1 in the alkyl moiety
is aralkyl or substituted acyl having ~4 carbon atoms, R1 is hydrogen or C7-4 alkyl, is hydrogen or haloke9, X is hydrogen or halodane, and Y is hydrogen or X and Y together represent a carbon-carbon bond, and W is alkoxycarbyl, cyano, cargyxamide or haloformyl having 1 to 4 carbon atoms in the alkoxy moiety. or, when X represents halodane, X and Y together represent a -C-O group) 2-azabicyclo(2,2,2), t-cutane derivatives. 2. As an active ingredient, the following formula I: phenylalkoxycarbonyl having 1 to 4 carbon atoms in the xy moiety, C1-6 alkyl, 1 in the alkyl moiety
is aralkyl or substituted acyl having ~4 carbon atoms, R1 is hydrogen or C1-4 alkyl, 2 is hydrogen or halogen, Xl-i is hydrogen or halogen, Y is hydrogen or X and Y together represent a carbon-carbon bond, W is alkoxycarbonyl, cyano, carpodixamide or haloformyl having 1 to 4 carbon atoms in the alkoxy moiety, or A pharmaceutical composition comprising at least one compound represented by halogen' (when represented by il-, X and Y taken together represent a -C-O group) 1 and customary pharmaceutical diluents or excipients. . 3, the following formula I: phenylalkoxycarbonyl having 1 to 4 carbon atoms in the xy moiety, 01-6 alkyl, 1 in the alkyl moiety
aralkyl or substituted acyl having ~4 carbon atoms; R4 is hydrogen or C1-4 alkyl; 2 is hydrogen or halodane; X is hydrogen or halogen; Y is hydrogen. , or X and Y together represent a carbon-carbon bond, W is alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, cyanide, carpodixamide or haloformyl, or X represents a halodane. When expressed, X
and Y together represent a -C-O group) 1 A method for producing a 2-azabicyclo[2,2,2)octane derivative represented by the following formula (■): (01-4 alkoxy) carbinyl group 1,2-dihydropyridine derivatives having the following formula: cH2=c -w (III) (wherein W and the 2nd digit defined above) and + + ) obtained by formula I (wherein A is the same meaning as defined above, and X and Y are both carbon - carbon bond and further W represents a haloformyl group), a compound of formula I (wherein X and Y together form a -C-0- group and further other substituents are defined above as 1) (with a defined meaning) into the corresponding halolactone,
After hydrolysis, optionally without isolation and/or optionally a2) Formula I (wherein A is C4-4 alkoxy (C1-4 alkoxy), and Y together represent a carbon-carbon bond, 2 is halogen, W is (c, ~4 alkoxy) carbonyl, cyan or Cal is a xamide group, and R1 has the same meaning as defined above. Yes, and/or as desired, Formula I (wherein A is Cl-47) 5I
n-phenyl(C1-4 alkoxy)car is a nyl group, X and Y together represent a carbon-carbon bond, 2 is hydrogen or halodane, W represents a haloformyl group, and R4 is defined above. ) is converted into the corresponding ester derivative by addition of an aliphatic alcohol having 1 to 4 carbon atoms and optionally isolated. Cal?
Hydrolyzing the compound of the nyl group, X and Y together represent a carbon-carbon bond, 2 is hydrogen or halogen, W represents a cyan group, and R4 has the meaning defined above. is converted into the corresponding acid amide, where W represents a xamide group, and enyl (01-
4 alkoxy) where Cal is a nyl group, X and Y together form a carbon-carbon bond, and R, Z and W have the meanings defined above) are protected under acidic conditions. By removing all the groups, the corresponding one of the formula ■ (wherein A is hydrogen, x and Y together represent a carbon-carbon bond, and the other substituents have the meanings defined above) and optionally further convert the resulting compounds into their acid addition salts, or optionally R2) by catalytic hydrogenation carried out with an excess of hydrogen, as conventionally prepared in step b1). The protecting group A is removed from the compound of formula (1) to obtain a compound of formula I (wherein the X-Y double bond is saturated and 2 is hydrogen), and optionally compounds of formula I (wherein A is hydrogen and X and Y together form a carbon-carbon bond) In addition, the X-Y double bond in the compound (R4゜2 and W have the meanings defined above) or their acid addition salts is catalyzed using a stoichiometric amount of hydrogen, and the hydrogen is saturated by addition. , further optionally converting the obtained compounds of formula I into their acid addition salts,
and 2 or, optionally, a compound of the formula (1) in which A is hydrogen, L, X and Y are hydrogen, or - together represent a carbon-carbon bond, and
z and W have the meanings defined above) or an acid addition salt thereof, by alkylating or acylating the compound of the corresponding formula I (wherein A is C1-6 alkyl, alkyl having 4 carbon atoms, or substituted acyl, furthermore R4e Z t X + Y and W have the meanings defined above. 4. A pharmaceutical composition comprising mixing a compound of formula (1) (wherein AtR41ZIXtY and W have the meanings defined in claim 3) with a pharmaceutical carrier or excipient. Production method.